Short Chain Fructo Oligosaccharides

Carcinogenicity

Description of key information

Clevenger et al. (1988) found no evidence of carcinogenicity in 104 week toxicty study.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Principles of method if other than guideline:

The chronic rat study was conducted by the Biosafety Research Center, Foods, Drugs and Pesticides (An-Pyo Center), Shizuoka-ken (437-12), Japan

GLP compliance:

not specified

Specific details on test material used for the study:

Neosugar is a mixture of fructooligosaccharides such as 1-kestose (GF2), nystose (GF3) and 1F-1-fructofuranosyl nystose (GF4). The sugar composition of Neosugar is approximately 37% GF2, 21% GF3 and 12% GF4.
Neosugar provided by Meiji Seika Kaisha Ltd.

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: 4 weeks of age
- Housing:
- Diet: ad libitum, modified NIH open formula rat and mouse diet (Oriental Yeast Co., Tokyo, Japan)
- Water: ad libitum
- Acclimation period: week of acclimation,


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24"C,
- Humidity (%): 50-60%.
- Photoperiod (hrs dark / hrs light): 12-hr light-dark cycle

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

104 weeks of treatment.

Frequency of treatment:

in diet

Dose / conc.:

50 000

Remarks:

in diet

Dose / conc.:

20 000 ppm

Remarks:

in diet

Dose / conc.:

8 000 ppm

Remarks:

in diet

No. of animals per sex per dose:

50 rats of each sex per dose

Control animals:

yes, concurrent no treatment

Details on study design:

After 1 week of acclimation, groups of 50 rats of each sex began receiving neosugar at concentrations of 0, 8000, 20,000, or 50,000 ppm in their diet. Because of the low toxicity of neosugar, the selection of the highest exposure concentration was based on the maximum volume of neosugar that could be incorporated as a food additive. The experiment was terminated after 104 weeks of treatment.

Observations and examinations performed and frequency:

Animals were observed at least twice daily. Body weights were determined weekly for the first 26 weeks and biweekly thereafter. Food consumption was determined weekly for all animals throughout the study. Food efficiency and neosugar intake were calculated from body weight and food consumption data.
At the termination of the study, surviving animals were anesthetized with ether, and blood samples were collected from the abdominal aorta. Hematology measurements were performed on all samples using a Coulter Counter Model SP (Coulter Electronics, USA). Blood smears fixed with methanol and stained with Wright-Giemsa were used for differential leukocyte counts and morphological evaluation. Blood chemistry measurements using serum were performed using a Centrifichem System 400 (Union Carbide Co., USA) except for Na, K, and Cl, which were measured with an automatic electrolysis analyzer (Toa Electronics, Tokyo, Japan). Brain, adrenals, heart, spleen, lungs, testes, liver, ovaries, and kidney weights were recorded for all animals surviving the length of the experiment. All animals, including those dying spontaneously or killed in a moribund condition, were necropsied. Tissues were fixed in 10% neutral buffer formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin.

Statistics:

A one-tailed Yates corrected Chi-square test was used to determine the significance of differences
in the: incidence of tumors. Logistic regression and Cochran-Armitage Chi-square(Zo)te sts for trend were used to determine significant dose-related trends. A significance level of P 5 0.05 was used in all analyses.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Tumors that occurred in greater than 5% incidence in any group are shown in
Table 1 (see other information). Pituitary adenomas, pheochromocytomas, thyroid C-cell adenomas, Langerhans' islet adenomas, and leukemias occurred commonly in control groups of both sexes. Interstitial cell tumors
of the testis were extremely common in control male rats, with an incidence greater than 80%. In
the female control group, mammary gland fibroadenomas and endometrial stromal polyps were
common. All of these tumors are considered to be spontaneous in F-344 rats.'*' '*)
Neosugar treatment did not increase the incidence of rare tumors in male or female rats. The incidence of spontaneous tumors in neosugar-treated animals was comparable to their incidence in concurrent controls, with the exception of pituitary adenomas. In male rats, the incidence of pituitary adenomas for the 0, 8000, 20,000, and 50,000 ppm dose groups was 20'70, 26%, 38%, and 440/0, respectively. The average background rate of pituitary adenomas in control male F-344 rats in this laboratory is 31%, with a range of 17-49%. Thus, the incidence of this tumor in male rats used in this experiment was within the historical range. However, pairwise comparisons between neosugar treatment groups and the concurrent control group showed the 20,000 and 50,000 ppm dose groups to have a significantly higher incidence of pituitary adenomas. To test for dose-related trends, two widely accepted trend tests were performed on these data. The Cochran-Armitage Chisquare test indicated a dose-response trend (P = 0.007), whereas logistic regression analysis showed no such trend (P = 0.51).
In female rats, the incidence of pituitary adenomas for the 0, 8000, 20,000, and 50,000 ppm dose
groups was 48%, 39%, 38'40, and 28%, respectively. The incidence of pituitary adenomas in females showed an apparent negative trend (opposite to that seen in males), but the difference between the high-dose group and control was not significant using a two-tailed Chi-square test (P = 0.06). The background rate in control female F-344 rats ranges from 24% to 49%, with a mean inciderice of 40%.

Details on results:

Neosugar did not increase the incidence of rare tumors in male or female rats, and pituitary adenoma. was the only spontaneous tumor that was significantly increased in a neosugar treatment
group. The increased incidence of pituitary adenomas occurred only in male rats. Pituitary adenoma
is one of the most frequently occurring spontaneous tumors in male and female F-344 rats based on the historical incidence in this laboratory as well as National Cancer Institute and National
Toxicology Program databases. The background incidence also is highly variable, ranging
from 20% to 50% in this laboratory. Although the incidence of this tumor in this experiment was well within the historical range for all male rats, the incidence in the two highest dose groups was significantly greater than the incidence in concurrent controls. However, the significance of a doserelated trend was equivocal in that one trend test showed a significant trend, whereas another test did not. If males are compared to females, a similar but opposite dose-response trend is noted.
This (dichotomy has no apparent biological basis. If male and female pituitary adenoma incidences
are combined, no significant across-dose group differences are found. All of these observations
point toward the conclusion that the higher incidence of pituitary adenomas in neosugar-treated
male rats is a chance artifact. Such chance artifacts can arise when large numbers of statistical comparisons are made. In this study, 54 comparisons were made, and one to three significant results
would be expected by chance alone at the significance levels of 0.01 and 0.05, respectively. It is unlikely, therefore, that neosugar was responsible for the occurrence of pituitary adenomas in male rats.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 50 000 ppm

Sex:

male/female

neoplastic lesions (e.g., pheochromocytomas, thyroid C-cell adenomas, leukemias, and pituitary adenomas) often occur spontaneously in F-344 rats. Further, the non-neoplastic lesions observed were common to aging rats of this strain as demonstrated by their historical control incidence. In the scFOS-treated animals, the incidence of rare tumors (those with incidences below 1%) in male or female rats was not increased. The incidence of spontaneous tumors in the scFOS-treated animals was comparable to that of controls, with the exception of pituitary adenomas. In the male rats, the incidence of pituitary adenomas for the 0-, 8000-, 20,000-, and 50,000-ppm dose groups was 20, 26, 38, and 44%, respectively, while the historic incidence of pituitary adenomas in F-344 male rats from the test laboratory ranges from 1 to 49%. While the incidence of this tumor in the present study was well within historical range for all male rats, the incidence in the two highest dose groups (20,000 and 50,000 ppm) was significantly greater than the incidence in controls. Further statistical analysis was carried out employing generally accepted tests of trend. Cochran–Armitage chi-square indicated a dose-response trend (p = 0.007), but logistic regression analysis showed no trend (p = 0.51), giving an overall equivocal result. In the female rats, a negative trend in the incidence of pituitary adenomas was recorded. Based on this analysis it was concluded that higher incidence of pituitary adenomas in males was not treatment related.

Conclusions:

The results of this study indicate that scFOS is not carcinogenic.

Executive summary:

The study carried out  was a combined 104-week chronic toxicity and carcinogenicity study with 104-week-old male and female Fischer 344 rats using scFOS. The animals were acclimatized for 7 days, then randomized into 4 groups of individually caged rats that received scFOS in their diet at concentrations of 0, 8000, 20,000, and 50,000 ppm, equivalent to 0, 341, 854, and 2170 mg/kg bw/day, respectively, for male rats and 0, 419, 1045, and 2664 mg/kg bw/day, respectively, for female rats.

The results of this study indicate that scFOS is not carcinogenic.